Summary Nonalcoholic fatty liver disease (NAFLD), a spectrum extending from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), is the most common cause of chronic liver disease in the Western world. It can lead to cirrhosis and hepatocellular carcinoma (HCC) and is independently associated with an increased risk of death due to cardiovascular and liver diseases. Consumption of high fat and cholesterol containing diet, the Western diet, is an important determinant of obesity and hence NAFLD. The molecular mechanism of NAFLD is gradually being elucidated leading to the evaluation of multiple interventional approaches in clinical trials. However, the optimum therapy is yet to be developed mandating more in-depth understanding of molecular pathogenesis of NAFLD, identification of novel molecules regulating this process and development of targeted therapeutic approaches. We unravel a novel role of Astrocyte elevated gene-1, also known as metadherin (MTDH) and LYRIC, in NASH. A transgenic mouse with hepatocyte-specific overexpression of AEG-1 (Alb/AEG-1) develops spontaneous NASH. NASH patients show increased AEG-1 expression in their liver compared to normal individuals. On the other hand hepatocyte-specific conditional AEG-1 knockout mouse (AEG-1CKOHEP) shows significant resistance to high fat diet (HFD)-induced steatosis. These findings indicate that AEG-1 might play a pivotal role in regulating initiation and progression of NASH. The long term objective of the present proposal is to obtain in-depth understanding of the molecular mechanism of NASH to develop effective therapeutic strategies. The immediate objective is to comprehensively interrogate the molecular mechanism by which AEG-1 promotes NASH and NASH-HCC and evaluate AEG-1 inhibition as a potential interventional strategy for NASH. We hypothesize that multiple events, such as preferential inhibition of nuclear receptors, translational regulation of lipid metabolism regulating genes and activation of inflammation, might contribute to AEG-1-induced NASH and AEG-1 inhibition might interfere with all these events thereby inhibiting development and progression of NASH. A comprehensive functional, biochemical and molecular analyses will be performed to address these hypotheses. Successful completion of the proposed studies will provide in-depth insight into the molecular mechanism by which AEG-1 promotes NASH and help establish AEG-1 inhibition as a potential effective therapeutic strategy for NASH and NASH-HCC. Thus the proposal has high mechanistic and translational significance.